Seminar – Yann PERCHERANCIER

Why study ion channels through the lens of BRET when patch-clamp exists? From bioelectromagnetics to drug screening.

Could bioluminescence resonance energy transfer (BRET), a technique widely used to investigate G protein-coupled receptors, reveal aspects of ion-channel biology that conventional electrophysiological approaches struggle to capture?

A question initially arising from bioelectromagnetics prompted the development of genetically encoded BRET biosensors capable of monitoring TRP-channel conformational rearrangements and interactions with regulatory partners, such as calmodulin, in real time and in living cells. Originally designed to investigate the effects of electromagnetic fields on ion channels, these molecular tools soon revealed a much broader potential.

Their application to TRPV1 drug screening uncovered unexpected regulatory mechanisms, challenging established views of calmodulin’s role in channel function and inspiring novel therapeutic strategies based on modulatory peptides. A second generation of BRET biosensors, designed to probe the ionic nanoenvironment of channel pores, subsequently revealed that certain ligands can differentially modulate ion permeability, opening new perspectives for ion-channel pharmacology through ligand bias and time-resolved pharmacological signatures.

Beyond these discoveries, BRET-based approaches could transform drug screening by providing access to particularly challenging targets, including intracellular ion channels within their native subcellular environments. Finally, returning to bioelectromagnetics raises another intriguing question: could electromagnetic fields, particularly pulsed fields, become new tools for modulating ion-channel activity, potentially paving the way toward drug-free therapeutic strategies?